PROJECT SUMMARY/ABSTRACT The Markey Cancer Center (MCC) was established more than 35 years ago as a university-based matrix cancer center at the University of Kentucky (UK), Kentucky's flagship institution of higher education. MCC is the only National Cancer Institute (NCI)-designated Cancer Center in Kentucky, a state of 4.4 million that leads the nation for all-site cancer incidence and mortality and serves as the MCC's catchment area. Over $347M in state, institutional, and philanthropic investment since recruitment of MCC Director Dr. B. Mark Evers (CS) in 2009 have supported significant research and resource expansion, enabling substantial new faculty recruitment, program development, renovation of clinical and shared resource space, and new state-of-the art instrumentation, as well as statewide education and community outreach efforts. The 119 MCC members draw from 28 departments in 8 UK colleges, with 28 new faculty recruited since 2013. Cancer-relevant research funding to MCC investigators exceeds $38.7M in total annual costs, an increase of $10.3M since 2012. Over the last 4 years, 9,357 subjects have been accrued to interventional trials. Members have published 851 cancer-focused publications since 2013, reflecting 28% intra-programmatic, 16% inter-programmatic, and 58% inter-institutional collaborations. Research is conducted within 4 MCC Research Programs: Cancer Cell Biology and Signaling; Cancer Prevention and Control; Drug Discovery, Delivery and Translational Therapeutics; and Genomic Instability, Epigenetics and Metabolism. Five Shared Resource Facilities (SRFs) facilitate cutting-edge research by providing robust infrastructure for specialized expertise and advanced methods: Biospecimen Procurement and Translational Pathology; Biostatistics and Bioinformatics; Cancer Research Informatics; Flow Cytometry and Cell Sorting; and Redox Metabolism. Two new SRFs (Behavioral and Community-Based Research and Oncogenomics) are in development. Significant achievements include: development of an NCI-sponsored early therapeutics program, including an active Molecular Tumor Board and Precision Medicine Center; expansion of the MCC Network from 8 to 24 sites; establishment of a regional Metabolomics Center (U24); award of 2 new cancer-related centers ? a Center of Biomedical Research Excellence (COBRE) in Cancer and Metabolism and a Center for Appalachian Research in Environmental Sciences; and expansion of community outreach/education initiatives across the state. MCC research focuses on Kentucky's most serious cancer burdens with emphasis on the ?distressed? Appalachian Kentucky region, where cancer incidence and mortality rates surpass those for the entire state. The MCC brings unique basic, clinical, and population research strengths to this mission. These strengths are integral to all MCC programs and collectively provide robust capacity to deliver transformative interventional research to an important underserved priority population, thereby contributing to national efforts to conquer cancer through discovery and clinical translation, cancer prevention, and community outreach.